Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

BELNEU Consortium, EU EOD Consortium, Stéphanie Philtjens, Sara Van Mossevelde, Julie van der Zee, Eline Wauters, Lubina Dillen, Mathieu Vandenbulcke, Rik Vandenberghe, Adrian Ivanoiu, Anne Sieben, Christiana Willems, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Barbara Borroni, Alessandro Padovani, Pau Pastor, Monica Diez-Fairen, Miquel AguilarAlexandre de Mendonça, Gabriel Miltenberger-Miltényi, Isabel Hernández, Merce Boada, Agustín Ruiz, Benedetta Nacmias, Sandro Sorbi, Maria Rosário Almeida, Isabel Santana, Jordi Clarimón, Alberto Lleó, Giovanni B. Frisoni, Raquel Sanchez-Valle, Albert Lladó, Estrella Gómez-Tortosa, Ellen Gelpi, Marleen Van den Broeck, Karin Peeters, Patrick Cras, Peter P. De Deyn, Sebastiaan Engelborghs, Marc Cruts, Christine Van Broeckhoven, on behalf of the BELNEU Consortium , and the EU EOD Consortium

Research output: Contribution to journalArticle

Abstract

We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD.

Original languageEnglish
JournalNeurobiology of Aging
DOIs
Publication statusAccepted/In press - Jan 1 2018

    Fingerprint

Keywords

  • Frontotemporal dementia
  • Genetic association
  • Granulin
  • Rare variants
  • Sortilin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

BELNEU Consortium, EU EOD Consortium, Philtjens, S., Van Mossevelde, S., van der Zee, J., Wauters, E., Dillen, L., Vandenbulcke, M., Vandenberghe, R., Ivanoiu, A., Sieben, A., Willems, C., Benussi, L., Ghidoni, R., Binetti, G., Borroni, B., Padovani, A., Pastor, P., Diez-Fairen, M., ... EU EOD Consortium, A. T. (Accepted/In press). Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia. Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2018.02.011